The objective of our application is to determine if exposure to polychlorinated biphenyls (PCBs) causes epigenetic transgenerational effects. There is extensive evidence that early life exposure to environmental chemicals can lead to disease outcomes in adult life. The negative effects of these exposures are believed to be reset in each generation, such that subsequent generations are unaffected by the exposure history of their parents and grandparents. However, evidence challenging this notion is growing, suggesting that in certain cases, environmental exposures affect multiple generations removed from the original insult, causing far- reaching consequences. It is still controversial whether thi phenomenon, known as transgenerational inheritance of acquired traits, occurs in mammals, though exposure to specific diets or nutritional factors, maternal stress, and certain environmental chemicals have all been reported to induce phenotypic changes observed at least two generations after exposure. We have shown that progeny of dams treated in utero with a mixture of coplanar and non-coplanar PCBs that simulates human exposure show cognitive deficits as adults. Other experimental evidence in rodents and primates strongly suggests a transgenerational impact of in utero exposure as the cause of abnormal fetal neurodevelopment and later childhood cognitive function. There is also compelling evidence of an association of PCB exposure with decreases in neurological function in infants and children, including Attention Deficit Hyperactivity Disorder. Similarly, maternal exposure during pregnancy to PCBs and other halogenated hydrocarbons has been associated with a higher incidence of congenital heart defects in the progeny and cardiac insufficiency later in life, linking fetal and adult cardiovascular disease. It remains to be determined if these health effects are caused by transgenerational or direct toxicity because studies have not been carried out to the F3 generation. In this application, we propose to address the hypothesis that exposure to PCBs during a critical window of development causes heritable transgenerational phenotypic changes in CNS and cardiac physiology associated with changes in DNA methylation patterns responsible for altered chromatin conformation and subsequent dysregulation of gene expression, detectable at least up to the F3 generation. In three Specific Aims, we will determine whether developmental PCB exposure during the time of germ-line specification will change neural or cardiac phenotypes transgenerationally and whether these changes will be associated with corresponding changes in the germ-line epigenome and affected tissue epigenomes and transcriptomes. Successful demonstration of transgenerational inheritance in response to in utero PCB exposure will transform our understanding of the health effects of these ubiquitous environmental pollutants.